The invention relates to a process for preparing and purifying 1,7xe2x80x2-dimethyl-2xe2x80x2-propyl-2,5xe2x80x2-bi-1H-benzimidazole which can be used on an industrial scale.
The preparation of 1,7xe2x80x2-dimethyl-2xe2x80x2-propyl-2,5xe2x80x2-bi-1H-benzimidazole by reacting 2-propyl-4-methyl-1H-benzimidazole-6-carboxylic acid with N-methyl-o-phenylene-diamine dihydrochloride is known from J. Med. Chem. (1993), 36(25), 4040-51 and International Patent Application WO 0063158.
1,7xe2x80x2-dimethyl-2xe2x80x2-propyl-2,5xe2x80x2-bi-1H-benzimidazole is of major importance as an intermediate product in the industrial synthesis of pharmaceutically active substances, particularly the pharmaceutically active substance telmisartan (Drugs of the future 1997, 22(10), 1112-1116). This gives rise to the need for a high level of purity. The purification process using ethyl acetate and diethyl ether known from the abovementioned literature is unsuitable as a large-scale process as diethyl ether, for example, presents a safety problem and requires careful handling on account of its toxicity, its tendency to form peroxides and the risk of explosion of its vapours, e.g. by electrostatic discharge.
The aim of the present invention is therefore to provide a process which can be used on an industrial scale for purifying the 1,7xe2x80x2-dimethyl-2xe2x80x2-propyl-2,5xe2x80x2-bi-1H-benzimidazole prepared by the abovementioned methods of synthesis and the variants thereof described in this specification.
Surprisingly it has been found that 1,7xe2x80x2-dimethyl-2xe2x80x2-propyl-2,5xe2x80x2-bi-1H-benzimidazole may be obtained in a highly pure form by a process suitable for use on an industrial scale if the essential purification steps are carried out using charcoal.
The invention therefore relates to a process which can be used on an industrial scale for purifying 1,7xe2x80x2-dimethyl-2xe2x80x2-propyl-2,5xe2x80x2-bi-1H-benzimidazole which has been prepared by reacting 2-propyl-4-methyl-1H-benzimidazole-6-carboxylic acid or the salts thereof with N-methyl-o-phenylene-diamine or the salts thereof, in which the crude product is treated with charcoal.
In a preferred process according to the invention 2-propyl-4-methyl-1H-benzimidazole-6-carboxylic acid is reacted with N-methyl-o-phenylene-diamine or the salts thereof, preferably in the form of a salt, preferably in the form of the phosphate, chloride or bromide salt, more preferably in the form of the phosphate or chloride salt, most preferably in the form of the phosphate salt, in the presence of methanesulphonic acid and phosphorus pentoxide.
Also preferred is a process wherein the reaction is carried out at a temperature of 125 to 145xc2x0 C.
In a particularly preferred process, the charcoal treatment purification step is carried out after the end of the reaction, hydrolysis and pH adjustment, by adding the reaction mixture to the charcoal.
Also particularly preferred is a process wherein the charcoal treatment purification step is carried out at a temperature of 70 to 80xc2x0 C.
Of particular importance is a process wherein the charcoal treatment purification step takes place at a pH of 0.7 to 1.2.
Also of particular importance is a process wherein the amount of charcoal used in a purification step is from 5 to 20 percent by weight of the 2-propyl-4-methyl-1H-benzimidazole-6-carboxylic acid used.
In a particularly preferred process, the purification step is repeated one to three times after the filtration or centrifugation of the reaction mixture.
In another particularly preferred process, after the purification by treatment with charcoal, the following steps take place in succession:
a) an organic solvent is added,
b) a base is added to obtain a pH of 5 to 6,
c) the aqueous phase is separated off,
d) the 1,7xe2x80x2-dimethyl-2xe2x80x2-propyl-2,5xe2x80x2-bi-1H-benzimidazole is separated from the organic phase by crystallization and subsequent filtration or centrifugation.
In another preferred process, isopropanol is used as the organic solvent in step a).
Also particularly preferred is a process wherein, in step b), the base is added at a temperature of 70 to 80xc2x0 C.
Also particularly preferred is a process wherein, in step d), the crystallization is carried out by the addition of water.
1,7xe2x80x2-dimethyl-2xe2x80x2-propyl-2,5xe2x80x2-bi-1H-benzimidazole is used in particular for preparing telmisartan. Telmisartan may be prepared using the method described in Drugs of the future 1997, 22(10), 1112-1116 according to the following synthesis diagram I: 
The following variants A, B, C, D and E are particularly preferred embodiments of the process according to the invention.
Variant A:
2-propyl-4-methyl-1H-benzimidazole-6-carboxylic acid (PMBC) and N-methyl-o-phenylenediamine (NMPD) or the salts thereof are added successively to a solution of an organic acid, preferably methanesulphonic acid, phosphorus pentoxide, thionyl chloride, sulphonyl chloride, acetic anhydride or polyphosphoric acid, preferably methanesulphonic acid, phosphorus pentoxide or thionyl chloride and/or mixtures or dilutions thereof with inert organic solvents, preferably N-methylpyrrolidinone, o-, m- or p-xylene, most preferably N-methylpyrrolidinone, with stirring at a temperature of 100 to 160xc2x0 C., preferably at 115 to 150xc2x0 C., particularly at 125 to 145xc2x0 C., most preferably at about 135xc2x0 C. PMBC and NMPD are used in a molar ratio of 1.0:0.5 to 1.0:2.0, preferably 1.0:0.7 to 1.0:1.5, more preferably 1.0:1.0.
The amount of organic acid and organic solvent is determined according to the amount of PMBC used. Up to 10 mol, preferably 2 to 8 mol, most preferably about 7 mol of organic acid and up to 2 mol, preferably 0.5 to 1.5 mol, most preferably about 1 mol of phosphorus pentoxide are used per mol of PMBC.
After the addition has ended the mixture is stirred for up to 10 hours, preferably 1 to 4 hours, most preferably 3 hours at a temperature of 100 to 160xc2x0 C., preferably 125 to 145xc2x0 C., preferably 135xc2x0 C. Then, in order to hydrolyse the excess acid component (anhydride, acid chloride), water is added to the organic acid used, for example phosphorus pentoxide, at a temperature of not more than 100xc2x0 C., preferably not more than 90xc2x0 C., in a ratio of 1.0:2.0 to 1.0:0.1, preferably 1.0:1.4 to 1.0:0.2.
After hydrolysis is complete, the pH is adjusted to 0.2 to 1.8, preferably 0.5 to 1.5, most preferably 0.7 to 1.2, more preferably 0.9 by the addition of a base, preferably sodium hydroxide, sodium carbonate or an amine, most preferably sodium hydroxide, sodium carbonate, ammonia, pyridine or triethylamine, most preferably sodium hydroxide solution or ammonia, more preferably sodium hydroxide. The temperature of the reaction mixture should not exceed 100xc2x0 C. during this addition and is preferably below 90xc2x0 C., most preferably from 70-80xc2x0 C.
While the temperature range remains constant, charcoal, preferably activated charcoal, preferably xe2x80x9cdry activated charcoalxe2x80x9d, xe2x80x9cmoist activated charcoalxe2x80x9d or xe2x80x9cgranulated activated charcoalxe2x80x9d, more preferably xe2x80x9cdry activated charcoalxe2x80x9d of the SX 2, SX Ultra or L2S grade is added to the reaction mixture to purify it. The activated charcoal preferably used in the process according to the invention may be obtained for example from the companies Norit, Atofina or Begerow. The amount of charcoal used in each purification step should be from 5 to 20 percent by weight, preferably from 6 to 15 percent by weight, most preferably from 8 to 12 percent by weight, more preferably about 10 percent by weight of the amount of PMBC used. The reaction mixture combined with charcoal is stirred for at least 5 min, preferably 5 to 60 minutes, preferably 8 to 50 minutes, most preferably 10 to 30 minutes at a temperature of max. 90xc2x0 C., preferably at 50 to 80xc2x0 C., most preferably at 70 to 75xc2x0 C. and then filtered or centrifuged, preferably filtered. The purification step may be repeated one to ten times, preferably one to five times, most preferably one to three times, preferably twice, with the reaction mixture which has been filtered or centrifuged in each case.
Then an organic solvent, preferably n-butanol, tert.-butanol, 2-methyl-propanol, n-propanol, isopropanol, ethyl acetate, dichloromethane, tetrahydrofuran or toluene, preferably n-butanol or isopropanol, most preferably isopropanol, is added to the reaction mixture with stirring. The amount of solvent is determined by the amount of PMBC previously used in the process and should be from 1:1 to 20:1, preferably from 1:1 to 10:1, most preferably from 1:1 to 5:1, preferably 3:1.
After the addition of the solvent has ended, a base, preferably sodium hydroxide, sodium carbonate or an amine, such as e.g. ammonia, pyridine or triethylamine, most preferably sodium hydroxide or ammonia, more preferably sodium hydroxide, is added at a temperature of not more than 100xc2x0 C., preferably at 50 to 90xc2x0 C., most preferably at 70 to 80xc2x0 C., more preferably at about 75xc2x0 C., to obtain a pH of 4 to 8, preferably 5 to 7, more preferably about 5 to 6. The mixture is stirred for at least 5 minutes, preferably 10 to 30 minutes, while the temperature is kept constant. After the phase separation has ended the aqueous phase is separated off and discarded.
To crystallise the product, acetone, ethyl acetate or water, preferably acetone or water, most preferably water, is added to the organic phase at ambient temperature or elevated temperature, preferably by refluxing. The amount of water used corresponds to 50 to 200 percent by volume, preferably 70 to 150 percent by volume, preferably percent by volume, most preferably 80 to 130 percent by volume, more preferably 120 percent by volume of the organic solvent used.
After the water has been added the mixture is cooled to a temperature of not more than 40, preferably 5 to 30xc2x0 C., most preferably 10 to 20xc2x0 C., more preferably 15xc2x0 C.
To isolate the product the mixture may be filtered or centrifuged. The product thus obtained may be treated with a washing solution containing water and one or more organic solvents selected from among acetone, n-butanol, tert.-butanol, cyclohexane, dichloromethane, ethyl acetate, isopropanol, methanol, 2-methyl-propanol, n-propanol, tetrahydrofuran, toluene or xylene, preferably acetone, isopropanol or ethyl acetate, most preferably isopropanol. As a rule the washing solution contains a ratio by volume of organic solvent/water of 1:0 to 1:10, preferably from 1:1 to 1:8, most preferably from 1:1.5 to 1:6, more preferably 1:2. Then the product is washed with water and dried, preferably in vacuo, at not more than 110xc2x0 C., preferably not more than 100xc2x0 C., most preferably at 75 to 90xc2x0 C.
Variant B:
As a modification of Variant A the strongly acidic reaction solution can be filtered through charcoal-filled containers or cartridges at a pH of about 0.2 to 1.8, preferably 0.5 to 1.5, most preferably 0.7 to 1.2, more preferably 0.9, instead of adding charcoal to the reaction solution or adding the reaction solution to the charcoal. The purification of the filtrate by extraction with an organic solvent and the additional working up may be carried out as described in Variant A.
Variant C:
As a modification of Variant A, instead of treating the acidic to strongly acidic reaction solution with charcoal, it is possible to treat the organic product solution with charcoal, for example to add charcoal, to add it to charcoal or filter it through charcoal, and the additional working up may be carried out as described in Variant A.
Variant D:
As a modification of Variant A, B or C the extraction may be carried out with a larger amount of the organic solvent, also at lower temperature, and this may be reduced again before the precipitation.
Variant E:
Another possible way of obtaining 1,7xe2x80x2-dimethyl-2xe2x80x2-propyl-bis-1H-benzimidazole as a pure product comprises directly precipitating the reaction product once the reaction has ended and hydrolysing it by the addition of a sufficient quantity of a base, preferably sodium hydroxide, sodium carbonate or an amine, such as e.g. ammonia, pyridine or triethylamine, most preferably sodium hydroxide or ammonia, more preferably sodium hydroxide or ammonia or adding the reaction solution to a solution of the base. After subsequent filtration the crude product, which may be dried, is dissolved in an organic acid or an organic solvent or a mixture of solvents selected from among methanesulphonic acid, isopropanol, n-butanol, ethyl acetate, methanol or toluene, preferably methanesulphonic acid or isopropanol, and the charcoal purification steps with subsequent further working up are carried out as described in Variant A. If methanesulphonic acid is used the precipitation may also be carried out by the addition of an alcoholic, e.g. methanolic, sodium hydroxide solution or by piping the product solution into an alcoholic, for example methanolic, sodium hydroxide solution. In this variant ascorbic acid or BHT (2,6-di-tert-butyl-4-methoxyphenol) may be added, preferably ascorbic acid.